University of Dundee

China Scholarship Council PhD programme - Characterising the immunomodulatory properties of CDK4/6 inhibitors in T cells

The School of Life Sciences at the University of Dundee, joint with the China Scholarship Council (CSC), is proud to be able to offer a scholarship programme for postgraduate research students. The scholarship covers all tuition fees and research fees and provides living expenses and one return flight ticket to successful candidates. There are up to 5 scholarships of 4 years duration available.

Project Description

Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) used in combination therapies to treat HR+/HER- breast cancer, leading to two-fold increases in mean progression-free survival versus placebo in patients. Following on the success of Palbociclib, clinical trials on new CDK4/6 inhibitors are ongoing to test their efficacy against other solid cancers, including small lung cancer. However, the cellular and molecular modes of action of these inhibitors are complex and are not well understood. 

In addition to targeting tumour cells, CDK4/6 inhibition promotes cancer regression by cell-intrinsic effects on immune cell function. CDK4/6 inhibition reduces regulatory T cell proliferation (1), while largely leaving the proliferation of CD8+ cytotoxic T cells (CTL) unaffected (1, 2). Reduced numbers of Tregs in the tumour microenvironment promote tumour cell killing by CTLs in CDK4/6 inhibitor-treated tumour mouse models (1). These results strongly suggest a role for CDK4/6 in regulating T cell function, potentially by phosphorylation of novel substrates.  

Our preliminary data suggest that CDK4/6 inhibitors promote complex changes in the abundances of cell surface receptors that regulate T cell function, including L-selectin (2). L-selectin is a critical cell surface receptor that controls T-cell homing and is dynamically regulated following T-cell activation.  

This PhD project aims to examine the immunomodulatory roles of CDK4/6 inhibitors comprehensively using quantitative biochemistry. The research will address the following questions: 

1. What are the effects of CDK4/6 inhibitors on T cell proliferation and phenotype? 

2. What are the targets of CDK4/6 in CD8+ T cells? 

3. How do CD8+ T cells (and not CD4+ T cells) bypass CDK4/6 inhibition? 

Global analysis of the proteome, phosphoproteome and secretome after CDK4/6 inhibition will provide an unbiased view of the phenotypic changes caused by these inhibitors. The prospective student will learn mass spectrometry-based proteomics (3) and tools for the analysis of large datasets. The project involves multi-disciplinary, collaborative work to assess CDK2 activity in T cells (Alexis Barr, Imperial College London) and in vivo analysis with mouse models (Ann Ager, University of Cardiff).  

References: (1) Goel et al. 2017, https://dx.doi.org/10.1038/nature23465; (2) Lewis, Cantrell, Zamoyska, Ly et al. unpublished; (3) Ly et al. 2017, https://doi.org/10.7554/eLife.27574